LEPR Deficiency

Disease Overview

Summary

LEPR deficiency is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Most people with this condition are obese before one year of age. Other symptoms include constant hunger and abnormal behaviors related to food. People affected with LEPR deficiency have low levels of sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. LEPR deficiency is caused by changes (mutations or variants) in the LEPR gene, which is responsible for making the receptor that interacts with a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of LEPR deficiency. Treatment is available for this condition using a drug called setmelanotide. With treatment, people with LEPR deficiency develop a normal appetite, lose weight and fat and can maintain the weight loss.

Introduction

LEPR deficiency is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed with this condition. It is one of several conditions that include early-onset obesity and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.

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Synonyms

• obesity, morbid, due to leptin receptor deficiency
• obesity due to leptin receptor gene deficiency
• leptin receptor deficiency
• LepR deficiency

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Signs & Symptoms

The symptoms of LEPR deficiency are different from person to person, with the most common symptom being early onset obesity. At birth, babies with LEPR deficiency have a normal weight. The earliest symptoms are constant hunger and excessive eating (hyperphagia) leading to rapid weight gain and obesity before one year of age. People with LEPR deficiency always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms may include low thyroid hormone and insulin resistance, which can lead to type 2 diabetes. Some children with LEPR deficiency get frequent infections because their immune system doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking.

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Causes

LEPR deficiency is caused by pathogenic variants (mutations) in the LEPR gene. The LEPR gene is responsible for making the leptin receptor, which works together with the protein, leptin. Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin receptors, leptin can’t do its job and the body doesn’t recognize when the body has enough energy and it’s time to stop eating.

LEPR deficiency is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

LEPR deficiency is a very rare disorder. In 2021, approximately 88 patients had been reported worldwide. It has been estimated that 1.34 per 1 million people may have this condition.

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Disorders with Similar Symptoms

LEPR deficiency is one of several rare inherited conditions that include early-onset obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.

Some of these conditions include:

Congenital leptin deficiency

Congenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.

PCSK1 deficiency

PCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to slightly diminish with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.

POMC deficiency

POMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.

Obesity due to melanocortin 4 receptor (MC4R) gene variants

This is the most common cause of early-onset obesity due to a single gene. People with only one MC4R gene variant are affected. Affected people show severe hunger and develop obesity during childhood. Weight and length are normal at birth. People with MC4R deficiency are often taller than average, which is one of the distinguishing features of this condition.

People with two MC4R gene variants develop an extreme form of obesity comparable to people with leptin or leptin receptor deficiency. During the first year of life, affected babies develop extreme hunger and rapidly gain weight. Other symptoms include increased insulin in the blood which can lead to type 2 diabetes. For more information see: Welcome to the Melanocortin 4 Receptor website at https://www.mc4r.org.uk/

There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:

Bardet-Biedl syndrome (BBS)

BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/

Alström syndrome

Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/

Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is characterized by symptoms and physical findings that vary in range and severity from person to person. Associated features include above-average birth weight, increased growth after birth (macrosomia), a large tongue (macroglossia), enlargement of certain internal organs (organomegaly) and abdominal wall defects (omphalocele, umbilical hernia or diastasis recti). BWS may also be associated with low blood sugar levels, distinctive grooves in the ear lobes (ear creases and ear pits), facial abnormalities and abnormal enlargement of one side or structure of the body (lateralized overgrowth). People with BWS also have an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor). Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of BWS occurs due to genetic changes that occur randomly. Inherited forms occur in about 5-10% of people with BWS. About 14% of people with BWS have an unknown cause. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal expression of certain genes that control growth on one part of chromosome 11 (BWS critical region). For more information on this disorder, choose “Beckwith-Wiedemann syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/beckwith-wiedemann-syndrome/

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Diagnosis

LEPR deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.

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Standard Therapies

Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to LEPR deficiency which has been diagnosed by genetic testing. This drug is given by daily injection. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss. People with LEPR deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH. The melanocortin pathway and energy homeostasis: From discovery to obesity therapy. Mol Metab. 2021 Jun; 48:101206.

Markham A. Setmelanotide: First Approval. Drugs. 2021 Feb;81(3):397-403.

Clément K, Mosbah H, Poitou C. Rare genetic forms of obesity: From gene to therapy. Physiol Behav. 2020 Dec 1;227:113134. Epub 2020 Aug 14.

Kleinendorst L, Abawi O, van der Kamp HJ, Alders M, Meijers-Heijboer HEJ, van Rossum EFC, van den Akker ELT, van Haelst MM. Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. Eur J Endocrinol. 2020 Jan;182(1):47-56.

Nunziata A, Funcke JB, Borck G, von Schnurbein J, Brandt S, Lennerz B, Moepps B, Gierschik P, Fischer-Posovszky P, Wabitsch M. Functional and Phenotypic Characteristics of Human Leptin Receptor Mutations. J Endocr Soc. 2018 Sep 17;3(1):27-41.

Dehghani, M. R., Mehrjardi, M. Y. V., Dilaver, N., Tajamolian, M., Enayati, S., Ebrahimi, P., Amoli, M. M., Farooqi, S., Maroofian, R. Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity. Europ. J. Med. Genet. 2018;61: 465-467.

Wasim M, Awan FR, Najam SS, Khan AR, Khan HN. Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity. Biochem Genet. 2016 Oct;54(5):565-72. doi: 10.1007/s10528-016-9751-z. Epub 2016 Jun 16.

INTERNET

Leptin Receptor Deficiency; LEPRD, Online Mendelian Inheritance in Man (OMIM). MIM 614963. Last updated: 5/01/2019. Available from: https://www.omim.org/entry/614963 Accessed Jan 11, 2023.

Leptin Receptor Deficiency. MedlinePlus. Updated Jul 1, 2016. Available from: https://medlineplus.gov/genetics/condition/leptin-receptor-deficiency/ Accessed Jan 11, 2023.

Obesity due to leptin receptor gene deficiency. Orphanet. Last updated May 2007. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=179494 Accessed Jan 11, 2023.

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